Approximately 550,000 Americans die annually because of exposure to cigarette smoke, either directly by smoking or indirectly by exposure to second-hand smoke. Addiction to cigarettes has created a tremendous healthcare burden for the United States; smokers and non-smokers alike shoulder the rising cost of healthcare insurance that results from the need to treat so many patients with smoking-related illnesses. Cigarette smoking is a potent delivery device for nicotine, the addictive substance in cigarette smoke. The addictive effects of nicotine are mediated through nicotinic acetylcholine receptors (nAChRs), which are ligand-gated cation-permeable ion channels. Nicotinic receptor activation stimulates neuronal excitability broadly throughout the brain, including cells in catecholaminergic nuclei such as ventral tegmental area (VTA), substantia nigra (SN), and locus coeruleus (LC). Dopaminergic cells in SN and VTA are important for nicotine-associated reward and reinforcement, while noradrenergic LC neurons are involved in learning, memory, and the ability to respond to a changing environment. Alpha4 and alpha6-containing receptors (not mutually exclusive) are key players in the nicotine-dependent activation of catecholamine release that occurs during addiction. alpha4beta2* (* denotes that other subunits may be present in the pentamer) activation is necessary and sufficient for reward and reinforcement in mice. Less is known about the alpha6 nAChR subunit and how it contributes to catecholamine, particularly norepinephrine (NE), release. Present questions include: Do locus coeruleus neurons express functional alpha6-containing receptors? How does activation of these receptors regulate membrane excitability in these cells? Does ACh regulate these cells by acting on somatic channels, presynaptic channels, or both? Do alpha6-containing receptors involved in LC excitability also contain alpha4 subunits? To answer these questions, alpha6-specific responses will be amplified and isolated. This will be done 1) indirectly by selectively activating alpha4alpha6-containing nAChRs using mice with hypersensitive alpha4 channels (Specific Aim 1), and 2) directly by generating (Specific Aim 2) and studying (Specific Aim 3) mice expressing hypersensitive alpha6 channels. Relevance: Understanding the role of nicotinic ACh receptors such as alpha6 will further contribute to our knowledge of nicotine addiction and related neural disorders. With a better understanding of addiction, better therapies to combat addictions such as smoking may be developed. [unreadable] [unreadable] [unreadable]